The present invention relates to novel tricyclic compounds useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention inhibit farnesyltransferase enzyme which activates ras proteins which in turn activate cellular division. More particularly, the novel compounds of the present invention are useful in the treatment of proliferative diseases such as, for example, cancer, restenosis, and psoriasis, and as antiviral agents.
Ras protein (or p21) has been examined extensively because mutant forms are found in 20% of most types of human cancer and greater than 50% of colon and pancreatic carcinomas (Gibbs J. B., Cell, 65:1 (1991), Cartwright T., et al., Chimica. Oggi., 10:26 (1992)). These mutant ras proteins are deficient in the capability for feedback regulation that is present in native ras and this deficiency is associated with their oncogenic action since the ability to stimulate normal cell division can not be controlled by the normal endogenous regulatory cofactors. The recent discovery that the transforming activity of mutant ras is critically dependent on post-translational modifications (Gibbs J., et al., Microbiol. Rev., 53:171 (1989)) has unveiled an important aspect of ras function and identified novel prospects for cancer therapy.
In addition to cancer, there are other conditions of uncontrolled cellular proliferation that may be related to excessive expression and/or function of native ras proteins. Post-surgical vascular restenosis is such a condition. The use of various surgical revascularization techniques such as saphenous vein bypass grafting, endarterectomy and transluminal coronary angioplasty is often accompanied by complications due to uncontrolled growth of neointimal tissue, known as restenosis. The biochemical causes of restenosis are poorly understood and numerous growth factors and protooncogenes have been implicated (Naftilan A. J., et al., Hypertension, 13:706 (1989) and J. Clin. Invest., 83:1419; Gibbons G. H., et al., Hypertension, 14:358 (1989); Satoh T., et al., Mollec. Cell. Biol., 13:3706 (1993)). The fact that ras proteins are known to be involved in cell division processes makes them a candidate for intervention in many situations where cells are dividing uncontrollably. In direct analogy to the inhibition of mutant ras related cancer, blockade of ras dependant processes has the potential to reduce or eliminate the inappropriate tissue proliferation associated with restenosis, particularly in those instances where normal ras expression and/or function is exaggerated by growth stimulatory factors.
Ras functioning is dependent upon the modification of the proteins in order to associate with the inner face of plasma membranes. Unlike other membrane-associated proteins, ras proteins lack conventional transmembrane or hydrophobic sequences and are initially synthesized in a cytosol soluble form. Ras protein membrane association is triggered by a series of post-translational processing steps that are signaled by a carboxyl terminal amino acid consensus sequence that is recognized by protein farnesyltransferase (PFT). This consensus sequence consists of a cysteine residue located four amino acids from the carboxyl terminus, followed by two lipophilic amino acids and the C-terminal residue. The sulfhydryl group of the cysteine residue is alkylated by farnesylpyrophosphate in a reaction that is catalyzed by protein farnesyltransferase. Following prenylation, the C-terminal three amino acids are cleaved by an endoprotease and the newly exposed alpha-carboxyl group of the prenylated cysteine is methylated by a methyl transferase. The enzymatic processing of ras proteins that begins with farnesylation enables the protein to associate with the cell membrane. Mutational analysis of oncogenic ras proteins indicate that these post-translational modifications are essential for transforming activity. Replacement of the consensus sequence cysteine residue with other amino acids gives a ras protein that is no longer farnesylated, fails to migrate to the cell membrane and lacks the ability to stimulate cell proliferation (Hancock J. F., et al., Cell, 57:1167 (1989), Schafer W. R., et al., Science, 245:379 (1989), Casey P. J., Proc. Natl. Acad. Sci. USA, 86:8323 (1989)).
Recently, protein farnesyltransferases (PFTs, also referred to as farnesyl proteintransferases (FPTs) have been identified and a specific PFT from rat brain was purified to homogeneity (Reiss Y., et al., Bioch. Soc. Trans., 20:487-88 (1992)). The enzyme was characterized as a heterodimer composed of one alpha-subunit (49 kDa) and one beta-subunit (46 kDa), both of which are required for catalytic activity. High level expression of mammalian PFT in a baculovirus system and purification of the recombinant enzyme in active form has also been accomplished (Chen W.-J., et al., J. Biol. Chem., 268:9675 (1993)).
In light of the foregoing, the discovery that the function of oncogenic ras proteins is critically dependent on their post-translational processing provides a means of cancer chemotherapy through inhibition of the processing enzymes. The identification and isolation of a protein farnesyltransferase that catalyzes the addition of a farnesyl group to ras proteins provides a promising target for such intervention. Recently, it has been determined that prototypical inhibitors of PFT can inhibit ras processing and reverse cancerous morphology in tumor cell models (Kohl N. E., et al., Science, 260:1934 (1993), James G. L., et al., Science, 260:1937 (1993), Garcia A. M., et al., J. Biol. Chem., 268:18415 (1993)). Furthermore, Blaskovich M., et al., "Proceedings Eighty-Sixth Annual Meeting American Association For Cancer Research," Mar. 18-22, 1995, Toronto, Ontario, Canada, Vol. 86, March 1995, Abstract 2578, disclosed a series of tetrapeptide inhibitors of farnesyltransferase which inhibited growth of tumor cells in nude mice.
Nagasu T., et al., "Proceedings Eighty-Sixth Annual Meeting American Association For Cancer Research," Mar. 18-22, 1995, Toronto, Ontario, Canada, Vol. 86, March 1995, Abstract 2615, disclosed a peptidomimetic inhibitor, B956, of farnesyltransferase which inhibits growth of human tumor xenografts in nude mice. Inhibition of tumor growth is correlated with inhibition of ras processing.
Thus, it is possible to prevent or delay the onset of cellular proliferation in cancers that exhibit mutant ras proteins by blocking PFT. By analogous logic, inhibition of PFT would provide a potential means for controlling cellular proliferation associated with restenosis, especially in those cases wherein the expression and/or function of native ras is overstimulated.
PCT Published Patent Application WO91/16340 discloses cysteine containing tetrapeptide inhibitors of PFT of the Formula CAAX.
PCT Published Patent Application WO94/26723 discloses a series of benzodiazepine derivatives as inhibitors of ras farnesyl:proteintransferase.
British Published Patent Application UK 980,853 disclosed compounds of the formula: ##STR2## and acid addition salts and quaternary ammonium derivatives thereof, in which:
Z represents a sulphur atom or a sulphoxide group (--SO--) or an amino group of the formula --(N--R.sub.1)--, wherein R.sub.1 represents a hydrogen atom or a protecting group, e.g., an acyl or a benzyl group, or an alkyl or alkenyl group containing up to 5 carbon atoms; PA1 R.sub.2 and R.sub.3, which may be the same or different, represent hydrogen atoms, or alkyl or alkenyl groups containing up to 5 carbon atoms, amino groups, monoalkylamino or dialkylamino groups, monoalkylaminoalkyl or dialkylaminoalkyl groups or monocyclic aryl or aralkyl groups, which aryl or aralkyl groups may be substitued with halogen atoms, trifluoromethyl groups, hydroxy groups or alkyl groups, alkoxy groups or alkylmercapto groups containing from 1 to 3 carbon atoms, or may together with the adjacent nitrogen atom form a cycloalkylamino group which may contain further heteroatoms, which heteroatoms, if nitrogen, may carry hydrogen atoms, alkyl groups, hydroxyalkyl groups or alkoxyalkyl groups, and R.sub.4 and R.sub.5, which may be the same or different, represent hydrogen or halogen atoms, or trifluoromethyl groups or hydroxy groups or alkyl, alkoxy or alkylmercapto groups containing from 1 to 3 carbon atoms for use as analgesics, chemotherapeutic agents, antihistamines, and as antiphlogistic and antioedemic agents. PA1 OR.sup.11 wherein R.sup.11 is hydrogen, or alkyl, PA1 SR.sup.11 wherein R.sup.11 is as defined above, PA1 CO.sub.2 R.sup.12 wherein R.sup.12 is hydrogen, alkyl, or benzyl, ##STR10## wherein R.sup.13 and R.sup.14 are independently the same or different and each is hydrogen, alkyl, or PA1 R.sup.13 and R.sup.14 are taken together with N to form a 5- or 6-membered ring optionally containing a heteroatom selected from the group consisting of N, S, and O or ##STR11## wherein R.sup.13 and R.sup.14 are as defined above, --CH.sub.2 --, --O--, --S(O).sub.m -- wherein m is zero or an integer of 1 or 2, ##STR12## or R is hydrogen, or alkyl; PA1 n is an integer of 1 to 5; PA1 R.sup.1 is heteroaryl; PA1 R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently the same or different and each is hydrogen, NO.sub.2, ##STR13## wherein R.sup.13 and R.sup.14 are as defined above, ##STR14## wherein R.sup.15 is hydrogen, alkyl, or aryl, CO.sub.2 R.sup.12 wherein R.sup.12 is as defined above, ##STR15## wherein R.sup.13 and R.sup.14 are as defined above, ##STR16## wherein R.sup.16 is alkyl, aryl, or arylalkyl, halogen, CN, OH, SR.sup.17 wherein R.sup.17 is hydrogen, or alkyl, SO alkyl, SO.sub.2 alkyl, alkoxy, benzyloxy, alkyl, or PA1 2- or 3-thienyl; PA1 2- or 3-furanyl; PA1 1-, 2- or 3-pyrrolyl; PA1 1-, 2-, 4-, or 5-imidazolyl; PA1 1-, 3-, 4-, or 5-pyrazolyl; PA1 2-, 4-, or 5-thiazolyl; PA1 3-, 4-, or 5-isothiazolyl; PA1 2-, 4-, or 5-oxazolyl; PA1 3-, 4-, or 5-isoxazolyl; PA1 1-, 3-, or 5-1,2,4-triazolyl; PA1 1-, 2-, 4- or 5-1,2,3-triazolyl; PA1 1- or 5-tetrazolyl; PA1 4- or 5-1,2,3-oxadiazolyl; PA1 3- or 5-1,2,4-oxadiazolyl; PA1 2-1,3,4-oxadiazolyl; PA1 2-1,3,4-thiadiazoyl; PA1 2-1,3,5-triazinyl; PA1 3-pyridinyl; PA1 3-, 4-, or 5-pyridazinyl; PA1 2-pyrazinyl; and PA1 2-, 4-, or 5-pyrimidinyl; or PA1 NH.sub.2, OH, SH, halogen, alkyl, or alkoxy. PA1 Y is --NH-- ##STR17## --O--, --S--, or --SO.sub.2 --; n is an integer of 1 to 5; PA1 R.sup.1 is a heteroaryl radical selected from the group consisting of: PA1 R.sup.3 and R.sup.4 are hydrogen or alkoxy; PA1 R.sup.6 and R.sup.7 are hydrogen, halogen, mercaptomethyl, hydroxymethyl, alkoxy, alkyl, or benzyloxy. PA1 n is an integer of 1 to 5; PA1 R.sup.1 is heteroaryl; PA1 R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently the same or different and each is hydrogen, NO.sub.2, ##STR19## wherein R.sup.13 and R.sup.14 are independently the same or different and each is hydrogen, alkyl, or PA1 R.sup.13 and R.sup.14 are taken together with N to form a 5- or 6-membered ring optionally containing a heteroatom selected from the group consisting of N, S, and O, ##STR20## wherein R.sup.15 is hydrogen, alkyl, or aryl, CO.sub.2 R.sup.12 wherein R.sup.12 is hydrogen, alkyl, or aryl, ##STR21## wherein R.sup.13 and R.sup.14 are as defined above, ##STR22## wherein R.sup.16 is alkyl, aryl, or arylalkyl, halogen, CN, OH, SR.sup.17 wherein R.sup.17 is hydrogen, or alkyl, SO alkyl, SO.sub.2 alkyl, alkoxy, benzyloxy, alkyl, or PA1 OR.sup.11 wherein R.sup.11 is hydrogen, or alkyl, PA1 SR.sup.11 wherein R.sup.11 is as defined above, PA1 CO.sub.2 R.sup.12 wherein R.sup.12 is hydrogen, alkyl, or benzyl, ##STR23## wherein R.sup.13 and R.sup.14 are as defined above or, ##STR24## wherein R.sup.13 and R.sup.14 are as defined above; with the proviso that at least two of R.sup.2, R.sup.3, R.sup.4, or R.sup.9 are hydrogen and at least one of R.sup.5, R.sup.6, R.sup.7, or R.sup.8 is hydrogen; PA1 OR.sup.11 wherein R.sup.11 is hydrogen, or alkyl, PA1 SR.sup.11 wherein R.sup.11 is as defined above, PA1 CO.sub.2 R.sup.12 wherein R.sup.12 is hydrogen, alkyl, or benzyl, ##STR34## wherein R.sup.13 and R.sup.14 are independently the same or different and each is hydrogen, alkyl, or PA1 R.sup.13 and R.sup.14 are taken together with N to form a 5- or 6-membered ring optionally containing a heteroatom selected from the group consisting of N, S, and O or ##STR35## wherein R.sup.13 and R.sup.14 are as defined above, and X, n, R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are as defined above may be prepared by reaction of a compound of Formula XI ##STR36## wherein X, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.10 are as defined above with a compound of Formula III using methodology previously described for preparing a compound of Formula Ia from a compound of Formula II and a compound of Formula III to afford a compound of Formula Ib.
British Published Patent Application UK 1,177,956 discloses a process of preparing compounds of the formula: ##STR3## wherein X is an oxygen or sulfur; one of R.sub.1 and R.sub.2 is hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, halogen or trifluoromethyl, and the other of R.sub.1 and R.sub.2 is hydrogen, (C.sub.1 -C.sub.6)alkoxy or halogen; Y is hydroxy, amino, (C.sub.1 -C.sub.6)alkylamino, di-(C.sub.1 -C.sub.6)alkylamino, 1-piperazinyl, 4-(C.sub.1 -C.sub.6)-alkyl-1-piperazinyl, 4-hydroxy-(C.sub.1 -C.sub.6)-alkyl-1-piperazinyl, pyrrolidino, (C.sub.1 -C.sub.6)alkyl-pyrrolidino, piperidino, (C.sub.1 -C.sub.6)alkyl piperidino, morpholino, or (C.sub.1 -C.sub.6)alkylmorpholino; R is (C.sub.1 -C.sub.6)alkyl; n is 2, 3, or 4; or the ##STR4## group taken together represents 1-piperazinyl, 4-(C.sub.1 -C.sub.6)-alkyl-1-piperazinyl, or 4-hydroxy-(C.sub.1 -C.sub.6)-alkyl-1-piperazinyl. These compounds were disclosed as having activity as tranquilizers and in some instances as antidepressants.
U.S. Pat. No. 3,539,573 discloses compounds of general Formula A: ##STR5## wherein Z denotes a member of the class consisting of bivalent sulfur, imino, and lower alkyl imino; R.sub.1 is a member of the class consisting of hydrogen and alkyl with 1 to 5 carbon atoms, and R.sub.2 is a member of the class consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, phenyl, R.sub.5 -substituted phenyl, aminoalkyl having from 1 to 5 carbon atoms, lower alkylated aminoalkyl having from 2 to 8 carbon atoms, amino, and lower alkylated amino; or R.sub.1 and R.sub.2 together with N form a member of the class consisting of 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, 4-(lower alkyl)-1-piperazinyl, 4-(lower hydroxyalkyl)-1-piperazinyl, and 4-(lower alkoxy-lower alkyl)-1-piperazinyl; and R.sub.3, R.sub.4, and R.sub.5 are members of the class consisting of hydrogen, halogen, hydroxy, trifluoromethyl, lower alkyl, lower alkoxy, and lower alkylthio; and (B) 11-basic substituted dibenzodiazepines and dibenzothiazepines having the general Formula B: ##STR6## wherein Z' denotes a member of the group consisting of sulfur, sulphinyl, and imino; R'.sub.1 represents a member of the group consisting of hydrogen, allyl, alkyl containing not more than 3 carbon atoms, hydroxyalkyl containing not more than 3 carbon atoms, alkoxyalkyl containing not more than 6 carbon atoms, and alkoyloxyalkyl containing not more than 6 carbon atoms; and R'.sub.2 is a member of the group consisting of nitro, amino, aminosulphonyl of the formula --SO.sub.2 NR'.sub.3 R'.sub.4 wherein R'.sub.3 and R'.sub.4 are the same or different members of the group consisting of hydrogen and methyl, alkylsulphinyl of the formula --SOR'.sub.5 wherein R'.sub.5 denotes alkyl with not more than 3 carbon atoms, and alkylsulphonyl of the formula --SO.sub.2 R'.sub.5 wherein R'.sub.5 denotes alkyl with not more than 3 carbon atoms; and (C) the nontoxic pharmaceutically acceptable acid-addition salts of (A) and (B).
These compounds are disclosed to be used as neuroplegics, neuroleptics, neuroleptic antidepressants, antiemetics, analgesics, sedatives, parasympathicolytics, and antihistaminics.
European Published Patent Application 0461869 discloses cysteine containing tetrapeptide inhibitors of PFT of the Formula Cys-Aaa.sup.1 -Aaa.sup.2 -Xaa.
European Published Patent Application 0520823 discloses cysteine containing tetrapeptide inhibitors of PFT of the Formula Cys-Xaa.sup.1 -dXaa.sup.2 -Xaa.sup.3.
European Published Patent Application 0523873 discloses cysteine containing tetrapeptide inhibitors of PFT of the Formula Cys-Xaa.sup.1 -Xaa.sup.2 -Xaa.sup.3.
European Published Patent Application 0528486 discloses cysteine containing tetrapeptide amides inhibitors of PFT of the Formula Cys-Xaa.sup.1 -Xaa.sup.2 -Xaa.sup.3 -NRR.sup.1.
European Published Patent Application 0535730 discloses pseudotetrapeptide inhibitors of PFT of the following two formulas: ##STR7##
Copending U.S. patent application Ser. No. 08/268,364 discloses a series of histidine and homohistidine derivatives as inhibitors of protein farnesyltransferase.
Compounds disclosed in the above references do not disclose or suggest the novel combination of structural variations found in the present invention described hereinafter.
We have surprisingly and unexpectedly found that a series of tricyclic compounds are inhibitors of farnesyltransferase and thus useful as agents for the treatment of proliferative diseases such as, for example, cancer, restenosis, and psoriasis, and as antiviral agents.